Download NSAIDs

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Chapter 22
Antipyretic-analgesic
and anti-inflammatory
drugs
2
introduction
3
Antipyretic-analgesic and antiinflammatory drugs
non-steroidal anti-inflammatory
drugs(NSAIDs)
Aspirin-like drugs
4
Antipyretic-analgesic and
anti-inflammatory drugs
• Be grouped in different classes
according to their chemical structures
• Share similar pharmacological effects
mechanism of action and adverse
reactions
• They all inhibit the biosynthesis of PGs
5
Membrane phospholipids
PLA2
Arachidonic
acid
NSAIDs
PGG2
glucocorticoid
COX
PGH2
PGI2
PGF2
PGE2
TXA2
(vascular (bronchial (vascular dilation; (vascular
dilation;
constriction) GI protection;
constriction;
platelet
pain,fever)
thrombosis)
disaggregate;
pain)
lipoxygenase
LTs
LTC4/
D4/E4
Bronchial
constriction ;
Alteration of
vascular
permeability
LTB4
chemotaxis
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The Different biological Activities
of the Products of AA
• PGI2:
vasodilation hyperalgesia
inhibit platelet aggregation
• TXA2: platelet aggregation and
vasoconstriction.
• PGE2: induce inflammation
fever and pain
vasodilation and hyperalgesia
• PGF2α: bronchial constriction and
vasoconstriction.
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The Different biological Activities
of the Products of AA
• LTs : allergy, bronch-constriction
leukocytotaxis
increase vascular permeability
induce inflammation
The different anti-inflammatory
mechanism
• Glucocorticoids : inhibit PLA2
• NSAIDs: inhibit COX and reduce the
production of PGs
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COX-1
Production
Function
Constitutive
Physiological function
gastric protection
platelet aggregation
COX-2
Inducible
Pathological function
facilitate inflammation
cause fever and pain
peripheral vessel regulation
renal blood distribution
NASIDs effects unwanted side effects
therapeutic effects
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【Three major actions of
NSAIDs】
Antipyretic effect
Analgesic effect
Anti-inflammatory effect
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1. Antipyretic effect :
mechanism
characteristics
clinical applications
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Mechanism
pathogen and toxins
neutrophils
endogenous pyrogens (IL-1,IL-6,TNF)
cox
NSAIDs
PGE2 (hypothalamus)
heat production
set point
heat dissipation
body
temperature
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Characteristics
① Central
②“Elevated” temperature — reduced
“Normal ” temperature — no influence
③ To what extent the COX inhibited is
consistent with the intensity of NSAIDs’s
pharmacological effects.
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Clinical applications
symptomatic treatment.
attention
As fever is a defense reaction of the body and heat pattern
is an important evidence in diagnosis, we should not hurry
to use antipyretic drugs for mild fever; but for high fever
and chronic fever, antipyretic drugs should be used in time
to reduce body temperature, avoid or alleviate the
complications.
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What is the difference between
NSAIDs and chlorpromazine in body
temperature regulation
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Comparison between
NSAIDs and Chlorpromazine
•
NSAIDs
Mechanism
Chlorpromazine
inhibit COX in
CNS → PGE2↓
inhibit thermoregulator
make it out of function
Effect
set point ↓
BT ↓
BT alters with the
environmental temperature
Clinical uses
fever
rheumatic fever
artificial hibernation
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2. Analgesic effect :
mechanism
characteristic
clinical application
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Mechanism
Other algesiogenic substance
(BK,histamine etc.)
injury
nociceptive
nerve endings
pain
+
PGs
NSAIDs
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
Bradykinin: cause pain through stimulating the
algesireceptors directly.

PG: (1) hyperalgesia
(2) PG(E1 E2 F2α) also have algesiogenic
effect
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Characteristics
① Peripheral
② mild to moderate pain.
③ No addiction or respiratory inhibition
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Clinical applications
① have good effects on chronic dull pain—
headache , toothache, neuralgia, muscle
pain,arthralgia,dysmenorrhea.
② are not effective for traumatic pain, severe
visceral pain—myocardial infarction or renal
or biliary colic
③ Non-narcotic and no euphoria.
No respiratory inhibition.
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What is the difference between NSAIDs
and analgesics in analgesic effect
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Drug
location mechanism
characteristics
representative
powerful ；
 sharp pain ；
 cause euphoria and
addiction ;
 respiratory inhibition
morphine
dolantin

Analgesics
NSAIDs
CNS
(+)opium
receptor
periphery
(-)PG
CNS(？) synthesis

moderate ；

chronic dull pain ；

not addictive

no respiratory
inhibition
aspirin
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3.Anti-inflammatory effect :
mechanism
characteristic
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3. Anti-inflammatory effect
Mechanism of inflammation:
phospolipids
injury
factor
PLA2
neutrophilic
granulocyte
cytokines
( IL-1,6,8 TNF)
arachidonic acid
induce
COX-2
PGs BK cell adhesion
molecules
inflammation
( redness, swelling, heat and pain )
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The role of PGs in inflammation
1.cause vasodilation and tissue edema
2.coordinate with bradykinin to cause
inflammation
♣ Mechanism of anti-inflammatory effect
(1)Reducing biosynthesis of
prostaglandins by inhibiting COX.
(2)inhibition of the expression of some cell
adhesion molecules
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Characteristics
① Peripheral
② They have certain effect on the control
of rheumatoid arthritis.
③ can’t effect a radical cure. They can
neither alter the course nor prevent
complications.
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【 NSAIDs classifications 】

According to selectivity for COX:
①Non-selective COX inhibitors
②Selective COX-2 inhibitors

According to chemical structures:
① Salicylates
② Anilines
③ Pyrazolones
④ Other organic acids
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Section 1
Nonselective COX inhibitors
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Salicylates
Anilines
Pyrazolones
Other organic acids
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Aspirin (Acetylsalicylic acid)
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【Pharmacokinetics】

Absorption: stomach，upper small intestine
aspirin
acetic acid＋salicylate

Distribution: in the form of salicylate
articular cavity, CSF and placenta
PPBR= 80~90%
CSF :cerebrospinal fluid
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
Metabolism: ＜1g,first-order kinetics,t1/2=2~3h;
≥1g,zero-order kinetics,t1/2=15~30h;
Still larger dosage→intoxication

Excretion: renal
the PH of urine: alkaline→85%;
acidic→5%
In salicylate acute intoxication, we can increase the
excretion of free salicylates by alkalizing the urine!
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【pharmacological actions
and clinical uses】
(1)Antipyretic-analgesic effect
(2)Anti-inflammatory and antirheumatic effects
(3)Platelet effect
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(1)Antipyretic-analgesiceffects:
most effective for fever and mild to
moderate pain
fever—profuse sweating,enough water
supplement
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(2)Anti-inflammatory and
antirheumatic effects:
①used in therapy and differential diagnosis
of acute rheumatic fever
②the preferred drug for rheumatoid arthritis
③adult: 3~5g/d
④In rheumatism treatment, we should
monitor the blood drug level
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(3)Platelet effect:
AA
blood vessel endothelium
platelet
PGI2
TXA2
(-)platelet
aggregation；
vascular
dilation
(+)platelet
aggregation；
vascular
constriction
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 Aspirin irreversibly acetylates and blocks platelet COX
→TXA2 biosynthesis(-)→platelet aggregation(-)→
thrombosis (-). (8-10d)
TXA2↓
Low dose
thrombosis is inhibited
PGI2 not affected
TXA2↓
High dose
unbeneficial for thrombosis inhibition
PGI2↓
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
Clinical uses:
①low aspirin dose (50~100mg) is recommended;
②prevent thrombosis:
cardiac or brain ischemic diseases.
angioplasty,coronary artery bypass grafting.
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Others
(1)Alzheimer,s disease(AD):
 AD is related to the over-expression of COX-2 in
brain.
 Aspirin 100 mg p.o. daily has repression effect
on AD
(2) Pregnancy-induced hypertension syndrome
and preeclampsia:
 is related to the increase of the ratio of TXA2 to
PGI2 in blood
 Aspirin 40-100mg p.o. daily can reduce the
incidence of PIH and the danger of
preeclamapsia
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【Adverse effects】
Gastrointestinal side effects
Disturbance of blood coagulation
Salicylism reaction
Hypersensitivity reactions
Reye’s syndrome
Nephrotoxicity
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1、Gastrointestinal side effects

gastric upset，gastric ulcer，gastric hemorrhage

Due to：
① direct irritation of the gastric mucosa
② high concentration→irritate CTZ: nausea and vomiting
③ inhibition of production of protective PGs

Countermeasures:
① take after meals, chew up the tablet,antacids
② enteric-coated aspirin

Contraindications: patients with peptic ulcer
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2. Disturbance of blood coagulation
 general dose—prolong bleeding time;
high dose or long-term use—inhibit prothrombin
biosynthesis (VitK can prevent)
 contraindications: hemophilia, pregnancy, sever hepatic
insufficiency, hypoprothrombinemia, VitK deficiency
 be stopped 1 week prior to surgery
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3. Salicylism reaction
 Large dosage(>5g/d)
 headache, vertigo, nausea, vomiting, tinnitus,
decreased vision and hearing；hyperpnea, acidbase disturbance, insanity.
 Therapy: ①aspirin be stopped at once,
②sodium bicarbonate infusions.
(fluid replacement)
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4. Hypersensitivity reactions
urticaria，angioneuro edema，allergic
shock
“aspirin asthma”: related to PG biosynthesis
inhibition
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When COX pathway is inhibited,LOX pathway is
strengthened,whose metabolites increase accordingly
CO
X
PGs
LOX
AA
LTs
NSAIDs
aspirin
asthma
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4. Hypersensitivity reactions
aspirin asthma
①mechanism: AA: → PG↓
→LTs↑→bronchospasm→asthma
②therapy: adrenalin ( )
antihistaminic, glucocorticoid (
)
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4. Hypersensitivity reactions
 contraindications: asthma
chronic urticaria
nasal polyps
48
5. Reye’s syndrome
 Severe hepatic dysfunction with
complication of encephalopathy
 Substitute aspirin with acetaminophen
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6. Nephrotoxicity
Also has been observed.
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Anilines
Acetaminophen (paracetamol):
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Similar antipyretic and analgesic
effects to aspirin,no significant antiinflammatory effect
 It inhibits synthesis of PG in CNS more
effectively than in periphery
 Less frequent gastrointestinal irritation

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Ibuprofen：

Less frequent gastrointestinal irritation

It can be slowly released into synovial fluid and
remains there with a high concentration

Widely used in rheumatoid arthritis(RA), and
osteoarthritis
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Section 2
Selective COX-2 inhibitors
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In 1998 and 1999,highly selective
COX-2 inhibitors (Celecoxib,Rofecoxib)
have been developed.
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Celecoxib

a highly selective COX-2 inhibitor，COX-2:COX1 =375:1

gastrointestinal adverse effects are less frequent

not affect TXA2 biosynthesis, but PGI2 synthesis
can be inhibited

Contraindications: patients with thrombosis
tendency
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Rofecoxib

a highly selective COX-2 inhibitor

does not inhibit platelet aggregation

is approved mainly for osteoarthritis
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Drugs used in gout
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purine
xanthine oxidase
uric acid
excretion
hyperuricemia
joints
kidney
arthritis
Kidney
damage
connective
tissue
Connective tissue
damages
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Treatment aim
①relieve the acute
Acute
gout
chronic
gout
gouty arthritis
attack
②control the
hyperuricemia
Drug
Mechanism
colchicine (-) inflammation
NSAIDs
Indometha (-) inflammation
cin
allopurinol
reduce the serum
level of uric acid
probenecid
↓uric acid
synthesis
↑uric acid
excretion
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allopurinol
purine
xanthine oxidase
uric acid
probenecid
excretion
hyperuricemia
NSAIDs
joints
kidney
Other
tissues
arthritis
Kidney
damage
Other tissue
damages
Indomethacin
colchicine
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